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Osteopontin is indispensible for AP1-mediated angiotensin II-related miR-21 transcription during cardiac fibrosis.

Lorenzen JM, Schauerte C, Hübner A, Kölling M, Martino F, Scherf K, Batkai S, Zimmer K, Foinquinos A, Kaucsar T, Fiedler J, Kumarswamy R, Bang C, Hartmann D, Gupta SK, Kielstein J, Jungmann A, Katus HA, Weidemann F, Müller OJ, Haller H, Thum T - Eur. Heart J. (2015)

Bottom Line: OPN and miR-21 were significantly increased in cardiac biopsies of patients with myocardial fibrosis.This was associated with enhanced cardiac collagen content, myofibroblast activation, ERK-MAP kinase as well as AKT signalling pathway activation and a reduced expression of Phosphatase and Tensin Homologue (PTEN) as well as SMAD7 in WT but not OPN KO mice.In vitro, Ang II induced expression of miR-21 in WT cardiac fibroblasts, while miR-21 levels were unchanged in OPN KO fibroblasts.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany lorenzen.johan@mh-hannover.de thum.thomas@mh-hannover.de.

No MeSH data available.


Related in: MedlinePlus

Proposed scheme of angiotensin II-induced osteopontin expression: angiotensin II leads to the expression of osteopontin in cardiac fibroblasts, which induces AP-1-mediated transcription of miR-21. Mature miR-21 targets and down-regulates PTEN, which subsequently leads to phosphorylation of AKT and nuclear exclusion of FOXO3a. In addition, miR-21 targets SMAD7, which results in phosphorylation of ERK. In cardiomyocytes, angiotensin II leads to the secretion of osteopontin, which induces the aforementioned mechanisms. Moreover, secreted osteopontin activates the PI3-kinase pathway as well as AKT phosphorylation. Taken together these mechanisms results in fibroblast survival and deposition of extracellular matrix (ECM).
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EHV109F6: Proposed scheme of angiotensin II-induced osteopontin expression: angiotensin II leads to the expression of osteopontin in cardiac fibroblasts, which induces AP-1-mediated transcription of miR-21. Mature miR-21 targets and down-regulates PTEN, which subsequently leads to phosphorylation of AKT and nuclear exclusion of FOXO3a. In addition, miR-21 targets SMAD7, which results in phosphorylation of ERK. In cardiomyocytes, angiotensin II leads to the secretion of osteopontin, which induces the aforementioned mechanisms. Moreover, secreted osteopontin activates the PI3-kinase pathway as well as AKT phosphorylation. Taken together these mechanisms results in fibroblast survival and deposition of extracellular matrix (ECM).

Mentions: We here show that OPN is essential in transcriptional activation of miR-21 in Ang II-induced cardiac fibrosis. The proposed mechanism of Ang II action and the role of OPN with respect to cardiac fibrosis are shown in Figure 6. The results are as follows: (i) OPN and miR-21 are increased in myocardial biopsies of patients with myocardial fibrosis related to aortic stenosis; (ii) OPN KO mice are protected from Ang II-induced cardiac fibrosis through a mechanism involving AP-1-mediated miR-21 transcription and subsequent pro-fibrotic action; (iii) miR-21 targets PTEN and SMAD7, thereby leading to activation of WT fibroblasts; (iv) Ang II induces OPN expression in WT fibroblasts; (v) OPN KO fibroblasts show impaired activation and expression of pro-fibrotic genes, unaltered levels of miR-21 and targets in response to Ang II; (6) Ang II leads to phosphorylation of ERK and AKT as well as nuclear Foxo3a exclusion, culminating in enhanced fibroblast survival; (vii) OPN is secreted from cardiomyocytes by Ang II stimulation; (viii) recombinant/secreted OPN leads to transcription of miR-21 through AP-1 activation, induces fibrotic gene expression and survival of WT fibroblasts, partly through PI3-kinase activation; (ix) in vivo overexpression of OPN by cardiotropic OPN-AAV9 amplifies Ang II-induced cardiac fibrosis; (x) the use of an LNA targeting miR-21 ameliorates Ang II-induced cardiac fibrosis.Figure 6


Osteopontin is indispensible for AP1-mediated angiotensin II-related miR-21 transcription during cardiac fibrosis.

Lorenzen JM, Schauerte C, Hübner A, Kölling M, Martino F, Scherf K, Batkai S, Zimmer K, Foinquinos A, Kaucsar T, Fiedler J, Kumarswamy R, Bang C, Hartmann D, Gupta SK, Kielstein J, Jungmann A, Katus HA, Weidemann F, Müller OJ, Haller H, Thum T - Eur. Heart J. (2015)

Proposed scheme of angiotensin II-induced osteopontin expression: angiotensin II leads to the expression of osteopontin in cardiac fibroblasts, which induces AP-1-mediated transcription of miR-21. Mature miR-21 targets and down-regulates PTEN, which subsequently leads to phosphorylation of AKT and nuclear exclusion of FOXO3a. In addition, miR-21 targets SMAD7, which results in phosphorylation of ERK. In cardiomyocytes, angiotensin II leads to the secretion of osteopontin, which induces the aforementioned mechanisms. Moreover, secreted osteopontin activates the PI3-kinase pathway as well as AKT phosphorylation. Taken together these mechanisms results in fibroblast survival and deposition of extracellular matrix (ECM).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543785&req=5

EHV109F6: Proposed scheme of angiotensin II-induced osteopontin expression: angiotensin II leads to the expression of osteopontin in cardiac fibroblasts, which induces AP-1-mediated transcription of miR-21. Mature miR-21 targets and down-regulates PTEN, which subsequently leads to phosphorylation of AKT and nuclear exclusion of FOXO3a. In addition, miR-21 targets SMAD7, which results in phosphorylation of ERK. In cardiomyocytes, angiotensin II leads to the secretion of osteopontin, which induces the aforementioned mechanisms. Moreover, secreted osteopontin activates the PI3-kinase pathway as well as AKT phosphorylation. Taken together these mechanisms results in fibroblast survival and deposition of extracellular matrix (ECM).
Mentions: We here show that OPN is essential in transcriptional activation of miR-21 in Ang II-induced cardiac fibrosis. The proposed mechanism of Ang II action and the role of OPN with respect to cardiac fibrosis are shown in Figure 6. The results are as follows: (i) OPN and miR-21 are increased in myocardial biopsies of patients with myocardial fibrosis related to aortic stenosis; (ii) OPN KO mice are protected from Ang II-induced cardiac fibrosis through a mechanism involving AP-1-mediated miR-21 transcription and subsequent pro-fibrotic action; (iii) miR-21 targets PTEN and SMAD7, thereby leading to activation of WT fibroblasts; (iv) Ang II induces OPN expression in WT fibroblasts; (v) OPN KO fibroblasts show impaired activation and expression of pro-fibrotic genes, unaltered levels of miR-21 and targets in response to Ang II; (6) Ang II leads to phosphorylation of ERK and AKT as well as nuclear Foxo3a exclusion, culminating in enhanced fibroblast survival; (vii) OPN is secreted from cardiomyocytes by Ang II stimulation; (viii) recombinant/secreted OPN leads to transcription of miR-21 through AP-1 activation, induces fibrotic gene expression and survival of WT fibroblasts, partly through PI3-kinase activation; (ix) in vivo overexpression of OPN by cardiotropic OPN-AAV9 amplifies Ang II-induced cardiac fibrosis; (x) the use of an LNA targeting miR-21 ameliorates Ang II-induced cardiac fibrosis.Figure 6

Bottom Line: OPN and miR-21 were significantly increased in cardiac biopsies of patients with myocardial fibrosis.This was associated with enhanced cardiac collagen content, myofibroblast activation, ERK-MAP kinase as well as AKT signalling pathway activation and a reduced expression of Phosphatase and Tensin Homologue (PTEN) as well as SMAD7 in WT but not OPN KO mice.In vitro, Ang II induced expression of miR-21 in WT cardiac fibroblasts, while miR-21 levels were unchanged in OPN KO fibroblasts.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany lorenzen.johan@mh-hannover.de thum.thomas@mh-hannover.de.

No MeSH data available.


Related in: MedlinePlus